Septic shock is a clinically catastrophic condition precipitated by an infection that leads to dysregulation of the host defense system. Cardiovascular failure is a key determinant of morbidity and mortality in patients with septic shock. The overall goal of this proposal is to improve the care of patients with sepsis by determining whether a protocol driven fluid and vasopressor protocol is a safe and effective method of resuscitating patients with cardiovascular failure from septic shock. Specific aim #1 will address whether a fluid and vasopressor protocol can achieve adequate circulation more rapidly and decrease length of vasopressor therapy compared with standard treatment in patients with septic shock. Treatment goals for mean arterial pressure in this protocol will be set in conjunction with a systematic review of the literature. In specific aim #2 the principal investigator will conduct a pilot trial to compare the safety and efficacy of norepinephrine compared with dopamine in patients with septic shock using this fluid and vasopressor protocol. Finally, in specific aim #3 we will characterize the role of genetic polymorphisms in the alpha and beta adrenergic receptors in patients with septic shock enrolled into the pilot study of specific aim #2. Jonathan Sevransky, the Principal Investigator of this K 23 application, is an Assistant Professor of Medicine in the Pulmonary and Critical Care Division of the Johns Hopkins University School of Medicine. He is formally trained in the clinical and basic mechianisms of sepsis and is fully committed to an academic career investigating the treatment of patients with septic shock, concentrating on the role of clinical treatment protocols for improving outcomes. The mentor of this application, Peter Provonvost, M.D., Ph.D., is an Associate Professor of Anesthesiology and Critical Care Medicine, Surgery, and Health Policy and Management and co-chair of the patient safety group of the Johns Hopkins Hospital. Dr. Pronovost is an internationally recognized leader in patient safety in the intensive care unit and has mentored previous K awards. He is currently leading 3 Federally funded grants that involve improving the care of patients in ICUs. The didactic and mentoring program outlined in this application is a result of close collaboration between Dr. Sevransky and Dr. Provonost, along with the other key personnel, and will provide a solid foundation for Dr. Sevransky's development as an independent investigator.